Carboxylic acid derivatives, in particular, amide compounds having carboxamide groups (—CONH—) are important compounds for pharmaceuticals, agricultural chemicals, dyes, high-molecular weight compounds or the like. Therefore, various synthetic methods thereof have been examined. For example, there is a method for producing amide compounds by dehydrating condensation of carboxylic acids and amine compounds in a water-containing solvent. However, in this case, the reaction in a water-containing solvent proceeds in a low yield, so that it is common to activate the carboxyl groups in an anhydrous solvent and then perform a reaction with amines.
In recent years, carbodiimide derivatives have been developed as a condensing agent that can be used in an aqueous solvent (Nozaki, Chemistry Letters, 1997, pp. 1-2). This is a method of synthesizing peptides in a water-containing solvent by using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) as a condensing agent. As a condensing agent that can be used in water or alcohols, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) has been reported (Kunishima et al., Tetrahedron, 2001, vol. 57, pp. 1551-1558), and this is used for production of amide compounds or ester compounds (International Application Publication No. WO/0053544). However, EDC and DMT-MM are both water-soluble and are condensing agents that are used in a uniform solvent system containing water. Therefore, it is not suitable to use them with a water-insoluble substrate.
On the other hand, a method for synthesizing peptides using a carbodiimide having a long chain alkyl group as a condensing agent at a reverse micelle interface between a hydrophobic solvent and water has been reported (Ranganathan et al., Journal of the American Chemical Society, 1989, vol. 111, pp. 1144-1145). Another method of dehydrating condensation at a micelle interface, which is lactonization and lactamization using amphiphilic Mukaiyama reagent (N-alkyl halopyridinium salt), has been reported (Rico et al., Journal of Organic Chemistry, 1994, vol. 59, pp. 415-420). However, all of these methods provide poor yields. Alternatively, it has been reported that esterification can be performed with Lewis acid thermodynamically in a hydrophobic field that is formed in an acid aqueous solution (Kobayashi at al., Journal of the American Chemical Society, 2001, vol. 123, pp. 10101). Since this reaction also proceeds even in the absence of water, the reaction is not performed at the interface. Accordingly, it cannot be said that the characteristics of the interface are utilized in the reaction. Thus, at present, other than the above agent, there is almost no condensing agent that can be used for dehydrating condensation of carboxylic acid at a water interface, which limits the type of carboxylic acids that can be utilized.